The AIDS epidemic is one of the most challenging problems in medicine in the 21st century (United Nations. 2004 Report on the global HIV/AIDS Epidemic: 4th global report. New York, U.S.A., 2004). The disclosure of the foregoing is incorporated herein in its entirety by reference. In addition, the entirety of the disclosures of each of the publications cited herein are also incorporated herein by reference. A retrovirus designated human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, or ARV. A common feature of retro-virus replication is the extensive post-translational processing of precursor polyproteins by a virally encoded protease to generate mature viral proteins required for virus assembly and function. Inhibition of this processing prevents the production of normally infectious virus. For example, Kohl (1988) demonstrated that genetic inactivation of the HIV encoded protease resulted in the production of immature, non-infectious virus particles. These results indicate that inhibition of the HIV protease represents a viable method for the treatment of AIDS and the prevention or treatment of infection by HIV.
The introduction of protease inhibitors (PIs) into highly active antiretroviral therapy (HAART), a combination therapy based on co-administration of PIs with reverse-transcriptase inhibitors, marked the beginning of a new era in HIV/AIDS chemotherapy. HAART treatment regimens have led to a significant decline in the number of deaths due to HIV infection in the developed World (Sepkowitz, 2001). The disclosure of the foregoing is incorporated herein in its entirety by reference. In addition, the entirety of the disclosure of each of the publications cited herein is also incorporated herein by reference. Unfortunately there are a number of factors that severely limit current HAART treatment regimens. High frequency of dosing, heavy pill burden and issues of tolerability and toxicity can lead to poor adherence to treatment (Waters, 2007). The need for more potent, less toxic drug regimens is quite apparent.
Currently available combination chemotherapy typically using two reverse transcriptase inhibitors (RTIs) and boosted protease inhibitors (PIs) or an integrase inhibitor or highly active antiretroviral therapy (HAART) for human immunodeficiency virus type 1 (HIV-1) infection and AIDS has been shown to suppress the replication of HIV-1 and significantly extend the life expectancy of HIV-1-infected individuals. Indeed, several recent analyses have revealed that mortality rates for HIV infected persons have become much closer to general mortality rates since the introduction of HAART, and that first line HAART with boosted PI-based regimens resulted in less resistance within and across drug classes.
However, the ability to provide effective long-term antiretroviral therapy for HIV-1 infection has become a complex issue since those who initially achieved favorable viral suppression to undetectable levels have experienced treatment failure. In addition, it is evident that even with these anti-HIV-1 drugs, only partial immunologic reconstitution is attained in patients with advanced HIV-1 infection and it is likely that HIV-1 will eventually acquire resistance to virtually any antiviral agents. Thus, it appears that the development of potent and drug-resistant-deferring antiviral agents will continue to be required for successful long-term control of HIV-1 infection and AIDS.
It is the rapid emergence of drug resistance however, that is proving to be a most formidable problem. Mutations causing drug resistance are thought to occur spontaneously, through the recombination of mixed viral populations, and also due to drug pressure, particularly when administered at sub-standard doses (Pillay, 2006; Grabar, 2000; Wainberg, 1998; Harrigan, 2005). A growing number of patients are developing multi-drug-resistant HIV-1 variants (Hertogs, 2000; Yerly, 1999). There is ample evidence that these viral strains can be transmitted. Thus, the development of antiretroviral agents able to maintain potency against resistant HIV strains has become an urgent priority.
The proteolytic enzyme, HIV-1 protease is essential for viral assembly and maturation (Roberts, 1990; Meek, 1990; McQuade, 1990). As a consequence, design of specific inhibitors for HIV-1 protease has become the subject of immense interest. In 1996, protease inhibitors (PIs) were introduced in combination with reverse transcriptase inhibitors to become highly active antiretroviral therapy (HAART) (Flexner, 1998; Cihlar, 2000). This treatment regimen significantly increased life expectancy, improved quality of life and decreased mortality and morbidity among HIV/AIDS patients. Despite these notable advances, the emergence of drug-resistant HIV-1 variants is severely limiting the efficacy of HAART treatment regimens. Therefore, development of new broad spectrum antiretroviral drugs that produce minimal adverse effects remains an important therapeutic objective for the treatment of HIV/AIDS (Wainberg, 2000; Hertogs, 2000).
Recently, structure-based design of inhibitors maximizing interactions within the active site protease back-bone were described, as was the development of nonpeptide inhibitors (1-2) that have shown picomolar enzyme affinity and exceptional antiviral activity against both wild-type and drug-resistant HIV-1 strains (Ghosh, 1998; Koh, 2003; Ghosh, 2002; Surleraux, 2005; Yoshimura, 2002; Koh, 2003). The X-ray crystallographic studies revealed that backbone conformation of mutant protease is minimally distorted compared to wild-type HIV-1 proteases. Without being bound by theory, it is believed herein that maximizing ‘back-bone binding’ may be an important design strategy to combat drug-resistance (Ghosh, 2008). Inhibitor 1 (Daraunavir, TMC-114) was recently approved by the FDA for the treatment of drug resistant HIV strains (on Jun. 23, 2006, the FDA approved new HIV treatment for patients who do not respond to existing drugs). More recently, it has been approved for all HIV/AIDS patients including pediatric AIDS patients (On Oct. 21, 2008, FDA granted traditional approval to Prezista (darunavir), co-administered with ritonavir and with other antiretroviral agents, for the treatment of HIV-1 infection in treatment-experienced adult patients. In addition to the traditional approval, a new dosing regimen for treatment-naïve patients was approved).
                1 (Darunavir, y=NH2)                    (Ki=16 pM; ID50=1.6 nM)                        2 (TMC-126, y=OMe)                    (Ki=14 pM; ID50=1.2 nM)                        
Described herein are novel PIs with functionalities capable of interacting with the protein backbone as well as the introduction of flexible macrocycles involving P1′-P2′-ligands.
It has been discovered that protease inhibitors (PIs) containing functionalities that interact with the amino acid backbones of the catalytic site of HIV-1 protease along with a flexible macrocyclic group involving P1′-P2′-ligands are potent inhibitors and also show high activity in more relevant cell-based assays. In addition, it has been discovered herein the such compounds including a flexible macrocyclic group involving P1′-P2′-ligands for effective repacking of the altered PI-binding cavity of protease that emerges upon side chain mutations in PI-resistant HIV-1 variants are potent inhibitors of such otherwise resistant variants. Without being bound by theory, it is believed herein that the high activity of the compounds described herein may be due to the dual mode of action in both inhibiting the proteolytic activity of the protease, as well as in inhibiting the dimerization of the protease.
In one illustrative embodiment of the invention, a compound having the formula
or a pharmaceutically acceptable salt, isomer, mixture of isomers, crystalline form, non crystalline form, hydrate, or solvate thereof is described, wherein
R2 and R3 are in each instance independently selected from the group consisting of hydrogen and a prodrug forming group;
R5 is alkyl, alkenyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, each of which is optionally substituted;
X4 is carbonyl, S(O) or SO2;
X5 is a bond, oxygen, unsubstituted nitrogen, substituted nitrogen, sulfur, S(O) or sulfone;
L1 and L2 are independently selected in each instance from the group consisting of alkylene, cycloalkylene, unsaturated alkylene, heteroalkylene, cycloheteroalkylene, and unsaturated heteroalkylene, each of which is optionally substituted;
W is a bond, (H)C═C(H), oxygen, sulfur, S(O), SO2, C(O), or optionally substituted nitrogen;
Q2 is a divalent carbocyle, heterocycle, aryl, or heteroaryl, each of which is optionally substituted with one or more substituents; and
Z is selected from the group consisting of monocyclic heterocycle, bicyclic heterocycle and tricyclic heterocycle, each of which is optionally substituted.
In another embodiment, the compound of any of the preceding embodiments wherein L1 and L2 are independently selected in each instance from the group consisting of alkylene, unsaturated alkylene, heteroalkylene, and unsaturated heteroalkylene, each of which is optionally substituted is described.
In another embodiment, the compound of any of the preceding embodiments wherein at least one of L1 or L2 is cycloalkylene or cycloheteroalkylene is described.
It is appreciated that the compounds described herein may be used alone or in combination with other compounds useful for treating such diseases, including those compounds that may operate by the same or different modes of action. Further, it is appreciated that the compounds and compositions described herein may be administered alone or with other compounds and compositions, such as other antiviral agents, immunomodulators, antibiotics, vaccines, and the like.